Oleaginous solutions of organic salts of bismuth



Patented July 23, 1935 PATENT OFFICE OLEAGINOUS SOLUTIONS OF ORGANIC SALTS OF BISMUTH Paul Emile Charles Goissedet and Robert Ludovic Despois, Choisy-Le-Roi, France, assignors to Societe Des Usines Chimiques Rhone-Poulenc,

Paris, France No Drawing. Application July 22, 1932, Serial No. 624,148. In Great Britain May 2, 1932 5 Claims.

The present invention relates to the production of new bismuth compounds and their oleaginous solutions for therapeutic use.

The importance of bismuth derivatives in the treatment of specific diseases has long been known.

It is also known (New and Non-Official Remedies, 1929, pages 92-94) that bismuth compounds cannot be used for intravenous'injection on account of the great toxicity of this metal when rapidly introduced into the blood stream. The usual method of treatment has for a long time been by intramuscular injection of a colloidal suspension of metallic bismuth or of one of its salts. The usual vehicle for such injections is a vegetable oil, preferably olive oil. This mode of injection has, however, frequently been objected to as liable to cause the deposition of bismuth or of its insoluble salts which are only resorbed with difficulty and for this reason give rise to irregular action.

Attempts to improve the technique of bismuth treatment have been directed to two points:

1. To obtain a compound of bismuth readily soluble in oils which can be as readily resorbed as the oil itself. Examples of such compounds are the naphthenate of bismuth (German Patent 441,871 of Merck) and the camphorcarbonate of bismuth (French Patent 657,694 of M. L. Picon).

2. To obtain a, bismuth compound which should be soluble in water, stable, and non-acidic, such as the substance known as Thiobismol (New and Non-Official Remedies, 1931).

The compounds of bismuth soluble in vegetable and animal oils which have been proposed up to now still have various drawbacks. The naphthenates are unstable in presence of water and their oily solutions are very rapidly gelatinized in contact with it. (Lebeau et Courtois, Trait de Pharmacie Chimique, vol. 2, page 482.) The camphorcarbonates are unstable when heated and readily lose carbon dioxide on sterilization.

According to the present invention we have found that stable solutions of bismuth salts in vegetable or animal oils containing up to 20% of bismuth may be prepared from bismuth salts containing at least one acid radicle of the general formula.

These oily solutions are stable even at a temperature of 120 0., and can be painlessly injected into the muscles and are rapidly resorbed.

In the above formula R represents a normal saturated alkyl group, R. represents an organic radicle containing fewer carbon atoms than R, and X represents one of the first two elements 5 of the 6th group of the periodic system (the oxygen-sulphur group).

In practice the a-halogenated fatty acids used as starting materials are prepared from the readily obtainable fatty acids. 10

In the same way-R is derived from readily obtainable alcohols and thiols. such as the normal primary aliphatic alcohols from CzHsOI-I to C1oH21OH and also the alcohols from phenylethylalcohol to hydrocinnamic alcohol and the corre- '15 sponding thiols. 1

There is no reason to believe that less applicable results would be obtained with products obtained when R and R are more complex, but for practical consideration it is not necessary to consider such compounds.

This invention is new, as it was so far known only (Picon, J. de Pharmacie et de Chimie, 8th series, vol. 10, page 45 that the neutral or basic bismuth salts of higher fatty acids or higher fatty oxyacids (octylate, palmitate, ricinole-ate) are extremely sparingly soluble or even insoluble in oils; one can therefore employ them in therapeutic doses only in the form of oil suspensions as, for example, in the case of the oleate (Hoflmann Laroche & 00., British Patent 206,- 487, Manufacture of emulsions of bismuth salts).

The solubility of the salts increases however, as we have found in a given series with the number of carbon atoms. One could not anticipate, for example, that the basic butyl-oxy-la-urate or the basic butyl thio-laurate of bismuth which contain only one acid radical containing 16 atoms of carbon to one atom of bismuth would have a solubility in oil so great that it is possible to prepare oily solutions of these salts containing more than 200 grammes of bismuth for one litre of the solution, and this in face of the well known fact that the basic bismuth palmitate 4r is insoluble in oils (Picon, Loo. cit.).

The oily solutions of these salts have a very great stability and can be heated for a certain time at 120 C., without any decomposition; they can be-kept for a very long time without undergoing any change. Especially, it is noteworthy to observe the great stability, even at elevated temperatures, of the salts of bismuth with alkyl, aryl or aralkyl-thio-acids and the total absence of any reaction between the sulphur and the bismuth although, as is well-known, they have a very great amnity for one another.

According to the present invention, the sodium. salt of the particular acid is caused to react with bismuth nitrate dissolved in a mixture of water and glycerine. If only one or two molecules of the sodium salt are used for one molecule of bismuth nitrate, one or two molecules of soda are added in such a way that there are always three atoms of sodium for one atom of bismuth.

The alkyl (aryl or aralkyl) oxy (or thio) acids are prepared by saponification of the corresponding esters. The latter can be easily obtained by the action of sodium derivatives of alcohols (or phenols) or of the alkyl (aryl or aralkyl) mercaptides of sodium on the zit-halogenated acids.

The following examples serve to show how the invention can be carried out in practice, but it is understood that the invention is not limited to these examples:

Example 1.62.4 grammes of oz-DhBIIYlOXY- caproic acid are dissolved in a mixture of 300 cc. of normal soda and 450 grammes of glycerine; to this solution is added a solution of 48.5 grammes of bismuth nitrate in 50 cc. of water and '70 grammes of glycerine. The bismuth salt which separates is extracted by benzenes; then by the addition of olive oil and distillation of the benzene there is obtained an oily solution of the a-phenyloxycaporate of bismuth which is stable even at C.

By replacing the 62.4 grammes of aphenyloxycaproic acid in this example by 41.6 grammes or 20.8 grammes of the same acid, oily solutions can be obtained in the same way of the basic bismuth phenyloxycaproates (containing two or one molecules of the acid for one atom of bismuth) which are as stable as the preceding bismuth phenyloxycaproate.

The a-phenyloxycaproic acid can be obtained by saponification of ethyl-a-phenyloxycaproate. This ester can be prepared by the action of sodium phenate on .ethyl-a-bromocaproate in a manner analogous to that which is employed for ethyl-aphenyloxybutyrate (Luchmann, Berichte, vol. 29, page 1421) It distils at C., under a pressure of 7 mm.

Example 2.86.4 grammes of a-blltYlthiOlflllIiC acid (prepared by the .saponification of ethyl-@- butylthiolaurate) are dissolved in a mixture of 300 cc. of normal soda and 450 grammes of glycerine; to this solution is added a solution of 48.5 grammes of bismuth nitrate in 50 cc. of water and 70 grammes of glycerine. After extraction of the bismuth salt which is formed by benzene and the addition of olive oil, the benzene is distilled off and an oily solution is thus obtained of bismuth a-butylthiolaurate which is stable even at 120 C. I

By employing only 57.6 grammes or 28.8 grammes of a-butylthiolauric acid in place of the 86.4 grammes, one can in the same fashion prepare oily solutions of basic bismuth m-butylthiolaurate (containing two or one molecules of the acid for one atom of bismuth). These oily solutions can be very concentrated and can contain more than 20 grammes of bismuth per 100 cc. of solution; they are as stable as the preceding ones. The ethyl m-butylthiolaurate can be prepared in very good yields by the action of sodium butylmercaptide on ethyl a-bromolaurate in alcoholic solution. It distils at C., under a pressure of 5 mm.

Example 3.--62.4 grammes of a-butyloxyphenylacetic acid (prepared by the saponification of ethyl a-butyloxyphenyl acetate) are dissolved in a mixture of 300 cc. of normal soda and 450 grammes of glycerine; to this solution is added a solution of 48.5 grammes of bismuth nitrate in 50 cc. of water and 70 grammes of glycerine. To the benzene solution of the bismuth salt which is obtained by extraction with benzene, olive oil is added; after distillation of the benzene there remains a stable oily solution of the bismuth salt.

Ethyl a-butyloxyphenyl acetate can be prepared in good yields by the action of sodium butylate on ethyl phenylchloracetate. It distils at 169 C., under a pressure of 15 mm.

What we claim and desire to secure by Letters Patent is:--

1. As a new composition of matter, an oily solution, containing up to 20% of bismuth, stable at a temperature of 120 0., and not depositing any solid or liquid at ordinary temperatures, having as solute a salt of bismuth containing at least one acid radicle of the formula H OinHzr--OOzH C4H9-S 3. As a new composition of matter/an oily solution containing from 5 to 20% of bismuth in the form of mono-a-butyl-thiolaurate of bismuth, having the formula 4. As a new composition of matter, an oily solution containing from 5 to 20% of bismuth in the form of di-a-butyl-thiolaurate of bismuth,

having the formula 5. As a new composition of matter, an oily solution containing from 5 to 20% of bismuth in the form of tri-a-butyl-thiolaurate of bismuth, having the formula PAUL EIWILE CHARLES GOISSEDET. ROBERT LUDOVIC DESPOIS. 

